The present invention is directed to a method of inhibiting the onset of acute radiation syndrome caused by the exposure of warm-blooded animals to a whole body dose of at least about 100 rads of X-radiation. The present invention is also directed to a method of inhibiting the onset of septicemia. Each of said methods comprising administering to a warm-blooded animal an effective amount of a pharmaceutical composition comprising refined detoxified endotoxin (RDE) in combination with a pharmaceutically acceptable carrier.
The exposure of a warm-blooded animal to a whole body dose of at least about 100 rads of X-radiation results in the onset of a complex set of symptoms termed acute radiation syndrome. The nature and severity of acute radiation syndrome is directly related to the dose of X-radiation to which the warm-blooded animal is exposed. However, it is generally recognized that the haemopoetic system, which is responsible for blood cell production, is the most severely damaged.
The single most important consequence of haemopoetic destruction following high level radiation exposure is that antimicrobial immunity is severely compromised with respect to both exogenous and endogenous microorganisms. Following irradiation with high levels of X-radiation, all warm-blooded animals, including man, are more susceptible to a broad spectrum of bacteria, viruses, protozoans, etc., as discussed in "Beneficial Effects of Endotoxins", edited by Alois Nowatny, pg. 127-148, Plenum Press, 1983.
In order to combat the toxic effect of X-radiation, it is necessary to stimulate the production and differentiation of granulocytes (granulopoiesis). Granulocytes are white blood cells such as macrophages, monocytes, eosinophils and basophils. It is known that the blood contains a factor, known as colony stimulating factor (CSF) which is necessary for granulopoiesis. Colony stimulating factor is described in Chervenick, P. A. et al., Science 118 164, 1972; and Golde, D. W. et al., Lancet 2, 1397, 1972, incorporated herein by reference. Therefore, the degree to which the blood exhibits colony stimulating factor is directly correlated to the ability of the body to withstand high doses of radiation.
Septicemia is a clinical syndrome in which infection is disseminated through the body by the blood stream. It is a potentially disastrous blood infection that can be caused by a variety of bacteria. It is a pathological state which results from the presence of microorganisms and/or their poisonous by-products in the blood stream.
A survey in 1974 reported that septicemia strikes 71,000 people in the United States annually resulting in death in approximately 25% of the cases. One of the major causes of septicemia is the result of post-operative infection resulting from endogenous bacteria from the respiratory or gastrointestinal tract (See Cruse, P. J. E., et al. Arch., Surg. 107, 106-210, 1973), incorporated herein by reference.
Refined detoxified endotoxin (RDE) is characterized as having no detectable 2-keto-3-deoxyoctanoate, between about 350 and 475 nmoles/mg of phosphorus and between about 1700 and 2000 nmoles/mg of fatty acids. RDE is a significant improvement over endotoxic extracts obtained from Enterobacteriaciae because RDE is detoxified and therefore does not contain the highly toxic components which have rendered endotoxic extracts unsuitable for therapeutic use (See Peptides as Requirements for Immunotherapy of the Guinea-Pig Line-10 Tumor with Endotoxins; Ribi, et al. Cancer Immunol. Immunother. Vol. 7, pgs 43-58 (1979)) incorporated herein by reference. The beneficial effects of RDE over other endotoxic extracts is described for example in U.S. Pat. Nos. 4,436,727 and 4,436,728; and Ribi, E. Journal of Biological Response Modifiers 3:1-9, Raven Press, (1984), incorporated herein by reference.
It is therefore an object of the invention to provide a method of inhibiting the onset of acute radiation syndrome in warm-blooded animals which are exposed to a whole body dose of at least about 100 rads of X-radiation using a therapeutic composition containing refined detoxified endotoxin.
It is another object of the invention to provide a method of inhibiting the onset of septicemia in warm-blooded animals using a therapeutic composition containing refined detoxified endotoxin.